Peptidic foldamers as specific protein ligands

描述（由申请人提供）：蛋白质之间的相互作用在生物学中起着至关重要的作用。特定蛋白的过表达或过表达可导致异常的相互作用水平，从而导致疾病。此外，许多病原体依靠蛋白质-蛋白质相互作用进行感染。因此，开发新的工具来抑制特定的蛋白质相互作用，或替代缺失或表达不足的伙伴分子，是一个相当重要的目标。这些分子可以作为阐明特定相互作用的生物学功能的有力工具，它们可以为新的治疗药物提供基础。拟议的研究旨在产生新的策略，以创造与天然蛋白质所显示的识别表面紧密结合的分子，这些表面进化成与其他蛋白质或大肽形成特定接触。我们寻找的化合物可能会破坏有害的蛋白质联系或增加不充分的相互作用水平。目前实现这些目标的方法是基于小分子、工程蛋白或中等大小的常规肽（即仅由α-氨基酸残基组成的肽）。尽管这些方法可能会取得成功，但每种方法都有局限性。例如，小分子通常不能在给定蛋白质上覆盖足够的表面积，以有效抑制与大伴侣蛋白的结合。用于治疗用途的蛋白质的生产和储存成本很高，长期使用可能会引发有害的免疫反应。中等大小的常规多肽通常在体内被蛋白酶迅速降解。我们的方法旨在补充这些现有的策略，以产生与目标蛋白质的特定表面结合的分子。我们专注于含有α-和ß-氨基酸残基的低聚物（“α/ß-肽”）。我们最近的研究表明，含有25-33% ß残基的α/ß-肽均匀分布在α残基之间，可以高度抵抗蛋白质水解。此外，我们还发现

DESCRIPTION (provided by applicant): Interactions between proteins play crucial roles in biology. Over- or under-expression of specific proteins can lead to aberrant interaction levels that contribute to disease. In addition, many pathogens depend on protein-protein interactions for infection. Thus, developing tools that lead to new inhibitors of specific protein-protein interactions, or molecules that can substitute for a missing or under-expressed partner, is a goal of considerable importance. Such molecules can serve as powerful tools for elucidating the biological functions of particular interactions, and they can provide the basis for new therapeutic agents. The proposed research is intended to generate new strategies for creating molecules that bind tightly to recognition surfaces displayed by natural proteins, surfaces that evolved to form specific contacts with other proteins or large peptides. The compounds we seek could disrupt deleterious protein associations or boost inadequate interaction levels. Current approaches to these goals are based on small molecules, engineered proteins or medium-sized conventional peptides (i.e., peptides comprised exclusively of α-amino acid residues). Although these approaches can be successful, each has limitations. For example, small molecules often cannot cover enough surface area on a given protein for effective inhibition of association with a large partner protein. Proteins engineered for therapeutic applications can be expensive to produce and store, and longterm use can provoke a deleterious immune response. Medium-sized conventional peptides are often degraded rapidly by proteases in vivo. Our approach is intended to complement these existing strategies for generating molecules that bind to specific surfaces on target proteins. We focus on oligomers that contain both α- and ß-amino acid residue ("α/ß-peptides"). Our recent work shows that α/ß-peptides containing 25-33% ß residues interspersed evenly among the α residues can be highly resistant to proteolysis. In addition, we have found that ß residues with a specific cyclic constraint can strongly stabilize an α-helix-like conformation. One aspect of the proposed research involves a search for alternative ß residue constraints that match non-helical local conformations commonly adopted by α-amino acid residues in folded proteins. This goal is being pursued via a combination of experimental and computational methods, in the context of inhibiting the association of a soluble signaling protein with its cell-surface receptors. Another aspect of the proposed research focuses on new agonists for B-family GPCRs. These studies allow us to determine whether α/ß-peptide analogues of natural agonists can display functional selectivity in their interactions with the target receptors ("biased agonism"). The over-arching goal of this program is to develop broadly applicable design strategies that can be implemented in many laboratories and that will be useful for many biomedically important protein-protein interactions.